Structural consequences of BMPR2 kinase domain mutations causing pulmonary arterial hypertension
Chaikuad A., Thangaratnarajah C., von Delft F., Bullock AN.
<jats:p>Bone morphogenetic proteins (BMPs) are secreted ligands of the transforming growth factor-β (TGF-β) family that control embryonic patterning, as well as tissue development and homeostasis. Loss of function mutations in the type II BMP receptor BMPR2 are the leading cause of pulmonary arterial hypertension (PAH), a rare disease of vascular occlusion and heart hypertrophy. To understand the structural consequences of these mutations, we determined the crystal structure of the human BMPR2 kinase domain at 2.35 Å resolution. The structure revealed an activate conformation of the catalytic domain that formed canonical interactions with the bound ligand Mg-ADP. Disease-associated missense mutations were mapped throughout the protein structure, but clustered predominantly in the larger kinase C-lobe. Modelling revealed that the mutations will destabilize the protein structure by varying extents consistent with their previously reported functional heterogeneity. The most severe mutations introduced steric clashes in the hydrophobic protein core, whereas those found on the protein surface were less destabilizing and potentially most favorable for therapeutic rescue strategies currently under clinical investigation.</jats:p>